Binding experiments suggest the presence of sigma binding sites that are distinct from any known brain neurotransmitter receptor or other drug binding site. These sites are unique in binding with high affinity both antipsychotic drugs and the unnatural (+)-enantiomers of opiates. Sigma binding is found in many brain areas, particularly brainstem regions associated with movement. One of these motor areas, the red nucleus, is of particular interest because it is rich in sigma sites, but largely lacking several other types of receptors that some sigma ligands bind (e.g. dopamine, alpha-adrenergic, PCP, and 5HT). We have demonstrated behavioral and electrophysiological effects of sigma ligands applied to this area of the brain. A better understanding of the nature and function of sigma receptors may explain the underlying mechanism of action of some of the certain racemic opiates such as pentazocine (Talwin) or dextromethorphan. Likewise, it is conceivable that some of the actions of antipsychotic drugs are mediated by these binding sites. However, binding studies, which demonstrated the existence of sigma binding sites, do not assure that they function as receptors (or other entities that regulate neuronal excitability). This proposal addresses the need for more work to establish the biological relevance of the sigma binding site. Behavioral, electrophysiological and biochemical studies are planned that will examine 1) the question of multiple sigma binding sites, their distribution in brain and across species; 2) the receptor selectivity of several novel compounds that exhibit high affinity for sigma sites. 3) the relationship between sigma binding and alterations in biological systems; 4) possible antagonistic relationships between sigma ligands (including putative irreversible ligands); and 5) the possibility that sigma sites can be regulated by chronic administration of potent sigma ligands. Studies into the nature of the sigma subtypes may provide a means to understand certain apparent contradictions that have arisen in the literature. Furthermore, if sigma binding sites play an important role in the neuronal signalling it should be possible (as our previous work suggests) to regulate their expression , and the efficacy of sigma ligands should be affected concomitantly. In addition, if the correlation between sigma binding and rural/dystonia stands up to the test of more ligands, this too would suggest biological significance. Finally antagonism between pairs of ligands would also suggest biological significance. The proposed studies therefore provide several bases on which to judge the function significance of sigma binding sites.